tbuckley/cabot-search huggingface dataset:
Abstract 1229: Deciphering molecular mechanisms of metastasis in renal cell carcinoma
Authors: Emily Nicole Arner, Melissa M. Wolf, Logan Vlach, Vania J. Sih, Dalton L. Greenwood, Scott Haake, Jeffrey C. Rathmell, Kimryn Rathmell
Journal: Cancer Research (2023)

Abstract Across human cancer, tumors that are high grade, poorly differentiated, and have undergone epithelial-to-mesenchymal transition (EMT) carry a worse prognosis with a high likelihood of metastasizing to distant organs. Despite significant research efforts, metastatic cancers and relapse remain the primary cause of cancer related deaths. In renal cell carcinoma (RCC), metastasis is present in one-third of patients at the time of diagnosis, and one-third of patients who initially present with locally advanced disease eventually develop local or distant recurrence following resection of the primary tumor, highlighting the need for new RCC therapies and further insight into the metastatic process. Using patient biopsies, immunohistochemistry, sequencing, and available clinical data in a cohort of RCC patients, we found that patients with more epithelial tumors have a significantly lower risk of recurrence. Unexpectedly, patients whose tumors had a mesenchymal protein signature had significantly increased infiltration of macrophages within their tumors. Additionally, increased macrophages in the primary tumor were significantly associated with a higher tumor stage at diagnosis and worse overall survival, suggesting that macrophages may play an important role in EMT in ccRCC. Furthermore, whole exome sequencing revealed that patients with increased macrophage infiltrate had a mutational loss of SETD2, a histone methyltransferase. Additionally, macrophages and EMT are also correlated, and tumor cell adhesion is reduced when SETD2 is lost in ccRCC patients. Further studies are needed to determine if SETD2 loss plays a role in the recruitment of macrophages to the tumor and EMT. Further characterization of the gene signatures, metabolic phenotypes, and immune cell infiltrate within these patient samples will lead to a better understanding of metastasis in an oncogene- and tissue-specific manner and thus lead to more efficacious therapies for metastatic patients. Citation Format: Emily Nicole Arner, Melissa M. Wolf, Logan Vlach, Vania J. Sih, Dalton L. Greenwood, Scott Haake, Jeffrey C. Rathmell, Kimryn Rathmell. Deciphering molecular mechanisms of metastasis in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1229.
Abstract 1220: Carcinogenic nickel(II) is a replication stressor causing genotoxicity via DNA incorporation of rNMPs
Authors: Casey Krawic, Sophia Valiente, Anatoly Zhitkovich
Journal: Cancer Research (2023)

Abstract Nickel(II) is a long-established inhalation carcinogen that causes lung and nasal tumors in humans and rodents. Despite its being a complete carcinogen, Ni(II) is DNA-unreactive and tested negative in the standard mutagenicity assays and consequently, is described as nongenotoxic. However, we have recently found that Ni(II) caused activation of the genotoxic stress-sensitive transcription factor p53, suggesting that this metal may possess some atypical, poorly detectable form(s) of genotoxicity. To determine what genotoxic or other cellular injury by Ni(II) upregulated p53, we examined multiple DNA damage responses and the role of several stress-sensitive kinases. We found that Ni(II)-induced phosphorylation and stabilization of p53 was mediated by ATR kinase but in its absence, by ATM kinase. Phosphorylation of p53 and CHK1 (another ATR target) occurred specifically in S phase, as determined by immunofluorescence and using synchronized cell populations. Inhibition of ATR strongly increased severity of replication stress and triggered activation of ATM kinase. Replication stress by Ni(II) was found to result from depletion of ribonucleotide reductase subunits through their higher turnover. We developed a novel fluorescent assay for detection of DNA-embedded rNMPs and found that Ni(II) induced a large increase in the DNA burden of ribonucleotides. The biological significance of DNA-incorporated rNMPs in Ni(II)-induced genotoxic responses was confirmed by the hypersensitivity of cells with inactivated ribonucleotide excision repair (RNAse H2 knockdown). Thus, our findings identified carcinogenic Ni(II) as a replication stressor inducing DNA incorporation of genotoxic rNMPs which are poorly detectable in the standard mutagenicity tests. Other protein-reactive carcinogen may also engage similar genotoxicity mechanisms. Citation Format: Casey Krawic, Sophia Valiente, Anatoly Zhitkovich. Carcinogenic nickel(II) is a replication stressor causing genotoxicity via DNA incorporation of rNMPs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1220.
Abstract 315: HPV-related genome rearrangements in head and neck cancer cell lines
Authors: Vera Mukhina, Alexa Anderson, Daria A. Gaykalova
Journal: Cancer Research (2023)

Abstract Cancer-associated papillomavirus (HPV) infection often leads to genomic rearrangements such as the integration of viral DNA into the human genome or formation of extrachromosomal DNA (ecDNA) circles with human-HPV DNA fusions, copy number alterations, translocations, inversions, or all at once. Such structures play a key role in cancer formation and progression by altering the expression of human and viral genes. They can also potentially increase genomic instability promoting new rearrangements, but little is known about how these rearrangements evolve during cancer. Unfortunately, short-read sequencing and standard assembly methods often fail to reconstruct HPV-induced rearrangements because of their repetitive nature. Long-read technology can potentially help to overcome this limitation.Here, we used Nanopore long-read whole genome sequencing to explore HPV structures in head and neck cancer cell line UPCI-SCC-090, known for its complex HPV rearrangements. We tested several protocols and methods on this cell line to estimate their impact on rearrangement detection. To study the dynamics of HPV rearrangements, we compared data from UPCI-SCC-090 to another cell line isolated later from the same patient (UPCI-SCC-152).As a result, we discovered a core set of UPCI-SCC-090 rearrangements involving chr 2,3,6 and 9, which remain robust across different tested protocols and methods, and these structures were consistent with previous studies. At the same time, we identified new minor rearrangements in UPCI-SCC-090 indicating heterogeneity within this cell line. The comparison with the UPCI-SCC-152 cell line demonstrated that most rearrangements were kept, but the overall profile of rearrangements changed. For example, UPCI-SCC-152 missed all HPV-induced alterations on chr 6.We concluded that the long-read approach failed to reconstruct all rearrangements completely but allowed us to study them in more detail on a single-molecule level and detect heterogeneity of HPV integrations within and between cell lines. We demonstrated that HPV-induced rearrangements formed a stable core that could persist for a long time with a minor group of variable rearrangements. Citation Format: Vera Mukhina, Alexa Anderson, Daria A. Gaykalova. HPV-related genome rearrangements in head and neck cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 315.
Abstract 3888: N-glycosylation-defective IL6 activates the SRC-YAP-SOX2 signaling to potentiate metastasis and TKI resistance in NSCLC
Authors: Chun Hua Hung, Shang-Yin Wu Wu, Hsuan-Heng Yeh Yeh, Chien-Chung Lin, Wu-Chou Su
Journal: Cancer Research (2023)

Abstract The IL6-GP130-STAT3 signaling pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130 receptor, its effect on the ligand IL6 remains unclear. In this study, we found that N-glycosylated IL6 primarily triggers JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (DeNG-IL6) induces shortened STAT3 activation and changes the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift promoted epithelial plasticity in vitro and metastasis in vivo, which were suppressed by specific inhibitors and shRNAs targeting SRC, YAP, and SOX2. EGFR TKI-resistant lung cancer cells secrete high levels of DeNG-IL6 via reduced N-glycosyltransferase gene expression and showed SRC-YAP activation. DeNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes, and signal expression in patient specimens. In summary, cell behaviors can be altered by modifying the N-glycosylation of IL6, and the glycosylation status of circulating IL6 might be a promising biomarker for monitoring the dynamics of lung cancer evolution. Citation Format: Chun Hua Hung, Shang-Yin Wu Wu, Hsuan-Heng Yeh Yeh, Chien-Chung Lin, Wu-Chou Su. N-glycosylation-defective IL6 activates the SRC-YAP-SOX2 signaling to potentiate metastasis and TKI resistance in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3888.
Abstract 3889: The role of CXCL1 in crosstalk between breast cancer cells with ESR1 mutations and lymphatic endothelial cells
Authors: Daniel Galke, Kideok Jin
Journal: Cancer Research (2023)

Abstract Various endocrine therapies have been developed such as selective estrogen receptor modulation (SERM), selective estrogen receptor downregulator (SERD) and ligand deprivation using aromatase inhibitors (AI). Tamoxifen, fulvestrant, and AIs are the most used adjuvant treatment for pre- and postmenopausal women with early-stage estrogen receptor positive breast cancer. Tamoxifen and AIs have widespread anti-neoplastic and chemopreventive effects, yet despite this, many breast cancers that are initially receptive ultimately become resistant and recur. There are many known underlying molecular processes that result in resistance, but no overarching pattern has yet been identified. Our previous research demonstrates that the crucial molecular and cellular players secreted from a crosstalk between stromal cells and breast cancer cells can control the development of the tumor and the metastatic process in breast cancer. Breast cancer metastasis involves lymphatic dissemination in addition to hematogenous spreading. Although stromal lymphatic vessels (LVs) serve as initial metastatic routes, roles of organ-residing LVs are underinvestigated. In this report, we demonstrated that crosstalk between ESR1 mutant cells (Y537S and D538G), and lymphatic endothelial cells (LECs), a component of lymphatic vessels, promoted ESR mutant cell growth and migration. To identify a critical secreted factor in this crosstalk, we performed the cytokine array in secretome of crosstalk between ESR1 mutant cells and LECs, and found that CXCL1 is highly secreted from LECs. Knockdown of CXCR2 in ESR1 mutant cells attenuated ESR1 cell migration in the conditioned media of LECs crosstalked with ESR1 mutant cells. To investigate a potential impact given the current clinical landscape of endocrine resistant breast cancer with ESR1 mutations, we performed a cell viability assay and migration assay using reparixin, CXCR1/2 inhibitor in co-culture with ESR1 mutant cells and LECs. Significantly, reparixin decreased ESR1 mutant cell viability and migration compared to vehicle. We found that the combination treatment of reparixin and Palbociclib and ribociclib significantly inhibited ESR1 mutant cell growth and migration compared the single treatment. These findings implicate CXCL1-CXCR1/2 signaling as a critical event in the growth of breast cancer with ESR1 mutation and metastasis. Therefore, we have provided evidence that supports the hypothesis that functional inhibition of the CXCL1 and CDK4/6 signaling pathway has the potential to circumvent endocrine resistant tumor growth and metastasis. Citation Format: Daniel Galke, Kideok Jin. The role of CXCL1 in crosstalk between breast cancer cells with ESR1 mutations and lymphatic endothelial cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3889.
Abstract 724: Leaving cancer patients behind for greener pastures: The clinical oncology workforce in Nigeria
Authors: Runcie C.W. Chidebe
Journal: Cancer Research (2023)

Abstract Background: For a population of over 201 million, Nigeria has only 4 doctors per 10,000 patients and 16.1 nurses, midwives per 10,000 patients, and less than 100 clinical oncologists for over 100,000 cancer patients. While Nigeria has one of the worst cancer burdens in the world and workforce shortage; 9 in 10 Nigerian physicians are seeking for opportunities to leave for the USA, UK and Canada. To improve oncology care in Nigeria, it may be important to understand the push and pull factors contributing to migration of clinical oncology (CO) workforce. Mathew (2018), Vanderpuye, et al., (2019), Balogun, et al., (2017), and Adebayo, (2016) have done research on CO; however, their studies were vastly focused on the African continent and not country-specific nor focused on the CO workforce in Nigeria. Aim: The aim of this study is to explore the push and pull factors to stay or leave clinical oncology workforce in Nigeria. Method: Using a mixed-method research approach, 80 participants completed the questionnaire and 9 participants responded to semi-structured interview. Multiple linear regression and Grounded theory was used for the data analysis. Results: The results show that CO workload and satisfaction were significantly related to turnover intention. The qualitative results showed that CO as a new area of specialization, mentorship, career growth and attractiveness of radiation science are pull factors. While, high CO workload, poor healthcare system, poor remuneration, corruption in the public sector, and few other themes are push factors. Empathy for patients, patriotism and sense of fulfilment unexpectedly emerged as retention factors in the study. Conclusion: Nigeria can improve patient’s treatment outcome by the reduction of CO workload through the employment of more CO. More CO can be available for employment when they are attracted, and their training is optimized. Those employed can be retained by improving working conditions and the introduction of work benefits. Our recommendations are that health leaders should create more CO training and awareness of CO in Nigeria. Citation Format: Runcie C.W. Chidebe. Leaving cancer patients behind for greener pastures: The clinical oncology workforce in Nigeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 724.
Abstract 3149: Prediction of metabolic drug targets for cancer patients with poor prognosis by using genome-scale metabolic models and survival analyses
Authors: Sang Mi Lee, GaRyoung Lee, Hyun Uk Kim
Journal: Cancer Research (2023)

Abstract Cancer metabolism has been extensively explored to identify biomarkers and novel drug targets for effective cancer treatment. In particular, it is expected that metabolism-derived data somehow reflects unique features associated with a cancer patient’s prognosis. Here, we introduce a computational framework that predicts metabolic drug targets by considering metabolites associated with poor prognosis. For inputs, the computational framework requires genome-scale metabolic models (GEMs) and survival data that represent each of cancer patients with diverse prognoses. GEM is a computational model that allows predicting fluxes of entire metabolic reactions in a patient-specific manner. By using this computational framework, a risk score, which reflects the prognosis of cancer patients, was first established on the basis of metabolites significantly associated with survival. Finally, metabolic reaction targets were predicted that could reduce the risk score (i.e., improving the prognosis) upon their knockdown in silico. In this study, this framework was applied to bladder cancer patients as a proof-of-concept demonstration, and predicted 13 metabolic reaction targets. These metabolic reaction targets were expected to be also effective to bladder cancer patients with poor prognosis. The computational framework developed in this study is distinct from previous drug targeting methods because it also considers unique metabolic features associated with cancer patients with poor prognosis in order to identify drug targets that are effective to both low-risk and high-risk groups of cancer patients. Citation Format: Sang Mi Lee, GaRyoung Lee, Hyun Uk Kim. Prediction of metabolic drug targets for cancer patients with poor prognosis by using genome-scale metabolic models and survival analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3149.
Abstract 4719: Alterations of chromatin structure and TGF-β signaling in ARID1A-mutated colon cancer cells
Authors: Jiwon Kim, Giyong Jang, Soo-Jin Lee, Sang Eun Lee, Sung-Yup Cho
Journal: Cancer Research (2023)

Abstract ARID1A, a subunit of the SWI/SNF complex which regulates gene expression by remodeling chromatin structure, is often mutated in various cancer and is known as a tumor suppressor gene. Many studies revealed the loss of ARID1A promotes tumor progression by activating PI3K-Akt signaling, but other pathways have not yet been fully elucidated. By analyzing RNA sequencing data and ATAC-seq data with ARID1A wild-type cell lines HCT116 and isogenic ARID1A Q456*/Q456* which has truncation mutations for ARID1A, we investigated the alterations of epigenomic and transcriptomic characteristics according to the loss of ARID1A. The overall openness of chromatin decreased in ARID1A Q456*/Q456* cells. Since SWI/SNF complex regulates chromatin structure and gene expression accordingly, we analyzed genes whose change of RNA expression and openness of chromatin in the same direction. The results showed 109 upregulated genes and 715 downregulated genes compared to wild type cell line with Padj &amp;lt; 0.05, |log2FC| &amp;gt; 0.58 from both RNA sequencing and ATAC-seq. To determine which gene sets are activated in the ARID1A-deficient cell line, the differentially expressed genes with consistent chromatin openness were subjected to Gene Ontology analysis. The upregulated genes in the ARID1A-deficient cell line were enriched in ‘Cell proliferation’ and ‘TGF-β signaling’. In addition, the expression of representative genes associated with TGF-β signaling increased in ARID1A-deficient cells. Our data suggests that loss-of-mutation in ARID1A significantly changes the chromatin structure, resulting in alterations of gene expression associated with cell proliferation and TGF-β signaling. Citation Format: Jiwon Kim, Giyong Jang, Soo-Jin Lee, Sang Eun Lee, Sung-Yup Cho. Alterations of chromatin structure and TGF-β signaling in ARID1A-mutated colon cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4719.
Abstract 3885: A secondary Gαq mutation confers resistance to Gαq inhibitors in uveal melanoma
Authors: Jiafang Ma, Meng Wang, Aashish Manglik, Boris C. Bastian, Xu Chen
Journal: Cancer Research (2023)

Abstract Uveal melanoma (UM) is a rare subtype of melanoma that originates from melanocytes of the choroidal plexus, ciliary body and iris. Despite successful treatment of the primary by radiation or surgery, 50% of UM patients develop metastases, mostly in the liver, as an invariably lethal complication. Over 90% of UM harbor activating mutations in the closely related GNAQ or GNA11 genes, mainly at codons Q209, compromising the GTPase activity. Mutant GNAQ and GNA11 can be successfully targeted by the cyclic depsipeptide YM-254890. To anticipate mechanisms of resistance that might arise under treatment with this novel class of Gαq inhibitors, we generated UM cell lines resistant to YM-254890 using an in-vitro cell culture system. Upon chronic growth suppression of a GNA11Q209L mutant UM cell line, we established 12 YM-254890 resistance clones. We identified a secondary GNA11F75Y mutation in one clone and GNA11Y192H mutations in the other 11 clones. The secondary mutations were present in cis with the original GNA11 Q209L mutations. To validate the functional role of these secondary mutations in conveying resistance, we engineered two double mutants, GNA11Q209L/F75Y and GNA11Q209L/Y192H, and introduced them into 293FT cells respectively and confirmed that both F75Y and Y192H convey resistance to YM-254890 treatment. The proliferation of YM-254890-resistant cell lines was still dependent on GNA11 and downstream PKC/MAPK signaling. Combined inhibition of PKC and MEK synergistically reduced cell viability in YM-254890 resistant UM cells. Analysis of the crystal structure of YM-2548890 in complex with GNAQ predicts both F75Y and Y192H mutations directly affect the binding of YM-254890 to Gαq. Our data suggest that direct targeting mutant GNAQ/11 is promising but will select for secondary mutations within GNAQ/11 that will result in resistance. Combinatorial targeting of other components in the Gαq signaling pathway will increase clinical efficacy. Citation Format: Jiafang Ma, Meng Wang, Aashish Manglik, Boris C. Bastian, Xu Chen. A secondary Gαq mutation confers resistance to Gαq inhibitors in uveal melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3885.